This invention relates to liquid handling and microfluidics.
The development of automated combinatorial chemistry systems and ultra-high throughput screening systems have dramatically increased the number of compounds per unit time being synthesized and screened in drug discovery programs. Such technology involves rapid handling of large numbers of very small samples. For example, thousands of new compounds per week may be produced, with each compound being concentrated in a total volume of only 50 microliters. Microliter amounts of sample often must suffice for hundreds of screening assays. Conventionally, aliquots of the concentrated, liquid sample are dispensed using xe2x80x9csip and spitxe2x80x9d liquid handling technology, diluted in an appropriate medium, and re-dispensed into an assay mixture, again using sip and spit technology. This xe2x80x9creformattingxe2x80x9d process adds complexity to the overall process, thereby increasing time and cost per assay. In addition, reformatting generates waste of valuable sample material.
The invention features a method of packaging a liquid for storage and metered dispensing of nanoliter or microliter volumes. The method includes: (a) providing a reservoir; (b) dispensing the liquid into the reservoir; and (c) incorporating a dispensing tap to form a reservoir/tap unit sealed against entry of air and leakage of the liquid. The dispensing tap includes a translatable metering tube that contains a tube end closure, a port, and a translatable piston. The reservoir can be sealed against entry of light. In some embodiments of the invention, the liquid is a solution of one or more chemical compounds. In some embodiments, liquid-contacting surfaces of the reservoir and tap are resistant to damage by acids, bases, salts and organic solvents. In some embodiments, the method further includes inserting a fill pin before dispensing the liquid into the reservoir. The fill pin can be inserted from below the reservoir and then removed by inserting the translatable metering tube from above the reservoir to replace the fill pin.
The invention also features a method of dispensing a metered, nanoliter or microliter amount of a liquid into a liquid-receiving unit. The method includes: (a) providing a sealed reservoir with an integrated dispensing tap that includes a translatable metering tube; (b) aligning the tap over the liquid-receiving unit; (c) actuating the tap so that it dispenses a metered, nanoliter or microliter amount of the liquid into the liquid-receiving unit. The translatable metering tube includes a tube end closure, a port, and a translatable piston. The metered amount of liquid can be from 10 nanoliters to 20 microliters, e.g., from 100 nanoliters to 2 microliters, or 50 nanoliters to 500 nanoliters. Preferably, the tap does not contact the liquid-receiving unit surface, and the dispensed liquid breaks contact with the tap before contacting the liquid-receiving unit surface. Preferably, the tap contains minimal, e.g., substantially zero, dead volume. In some embodiments, actuating the tap includes: translating the tube so that the port is inside the reservoir; drawing liquid from the reservoir through the port and into the tube; translating the tube so that the port is outside the reservoir; and expelling liquid from the tube, through the port. The liquid can be drawn into the tube by translating the piston upward. The liquid then can be expelled from the tube by translating the piston downward. The method can include propelling the expelled liquid away from the port and toward the liquid-receiving unit surface. Such propelling can be accomplished by applying a suitable propelling fluid to the expelled liquid. The propelling fluid can be a propelling liquid, e.g., an aqueous liquid or an organic solvent; or a propelling gas, e.g., air, nitrogen or argon. The dispensed liquid can be, e.g., a solution of one or more chemical compounds. The liquid-contacting surfaces of the reservoir and tap can be made of a material resistant to damage by acids, bases and organic solvents.
The invention also features devices for storing and dispensing metered, nanoliter or microliter amounts of liquid into a liquid-receiving unit.
An offset nozzle-type device includes: a sealed reservoir with an integrated metering tap. The tap includes a metering tube and a fluid output channel. The metering tube is translatable between a fill position inside the reservoir and an expel position outside the reservoir. The metering tube includes: (2) a tube end closure in a lower portion of the tube, (2) a port above the tube end closure, and (3) a piston in an upper portion of the tube. The piston is movable between a down position that seals the side port and an up position above the port. The fluid output channel has an upper portion in fluid communication with the port when the tube is in the expel position and a lower portion terminating in a nozzle tip. Movement of the piston from the up position to the down position can displace from 10 nanoliters to 20 microliters, e.g., from 20 nanoliters to 2 microliters, or 50 nanoliters to 500 nanoliters. The device can include a compressed gas inlet port in fluid communication with the fluid output channel at a point upstream of the port when the tube is in the expel position.
An in-line nozzle-type device includes a sealed reservoir with an integrated metering tap. The metering tap includes a metering tube and a nozzle. The metering tube is translatable between a fill position inside the reservoir and an expel position outside the reservoir. The metering tube includes: (2) a tube end closure in a lower portion of the tube, (2) a port above the tube end closure, and (3) a piston in an upper portion of the tube. The piston is movable between a down position that seals the port and an up position above the port. The nozzle includes a fluid output channel through which the tube extends when in the down position. The fluid output channel has an upper end in fluid communication with a compressed gas path, and a lower end terminating in a nozzle tip. Movement of the piston from the up position to the down position can displaces from 10 nanoliters to 20 microliters, e.g., from 20 nanoliters to 2 microliters, or 50 nanoliters to 500 nanoliters.
A nozzleless-type device includes a sealed reservoir with an integrated metering tap. The metering tap includes a metering tube. The metering tube is translatable between a fill position inside the reservoir and an expel position outside the reservoir. The metering tube includes: (2) a tube end closure in a lower portion of the tube, (2) a port above the tube end closure, a (3) a piston in an upper portion of the tube, and (4) a lower end. The piston is movable between a down position that seals the port and an up position above the port. A compressed gas path, which includes one or more compressed gas outlets located above the port, is located to deliver a downward gas stream across the port, when the metering tube is in the expel position. Movement of the piston from the up position to the down position can displace from 10 nanoliters to 20 microliters, e.g., from 20 nanoliters to 2 microliters, or 50 nanoliters to 500 nanoliters. In some embodiments, the lower end of the metering tube is tapered to a point.
As used herein, xe2x80x9cliquid-receiving unitxe2x80x9d (LRU) means: (a) a defined or addressable area on a flat liquid-receiving surface, e.g., a glass slide; or (b) a depression or well in a liquid-receiving container, e.g., a microtiter plate, or (c) a receptacle, e.g., a test tube, vial, or bottle.
As used herein, xe2x80x9creservoir/tap unitxe2x80x9d means a single tapped reservoir.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.